What is an antibody drug conjugate (ADC) ?
Antibodies are proteins that occur normally in the body; there are literally millions of them. They help maintain the first line of defense when foreign substances enter the blood stream. Typically, they bind a specific antigen and when they do, they aid in neutralizing the foreign substance.
Antibodies have several sites that occur naturally in the polypeptide sequence that allow drugs to be attached to them. These are most often cysteine residues, but one can also program in a recombinant site for attachment. When a drug is attached to an antibody, it is known as an antibody drug conjugate (ADC).
ADCs represent one of the most exciting areas of drug development in cancer today. There are currently two approved ADCs (Kadcyla, Adcetris) – but there are many in clinical development that show great promise in helping to provide treatment for cancer. The hope is that some of these may actually cure cancer.
Present State of ADCs
All of the approved ADCs, and indeed many of those in development, contain 2-4 drugs (toxins, sometimes called a “warhead”) attached to them. Thus, most of the ADCs have a drug-antibody ratio (DAR) of ~ 4. That is because the four attachment sites used for conjugation of the toxin do not alter the antibody appreciably, and it can still bind with high affinity to its target antigen. Early attempts to attach more than four toxins to antibodies often resulted in changes that were no longer suitable for development of them as a targeted therapy. Thus, the current technology is somewhat limited.
The Future of ADCs
All of the ADCs that are approved target cancers that express a high density of the target antigen on the surface of the cancer cell. For example, Kadcyla targets the HER-2 receptor on breast cancer – and this target has several hundred thousand copies expressed on the surface. Likewise, Adcetris targets a cancer cell with hundreds of thousands of copies of CD-30 on the surface.
But what if the cancer has only a few hundred, or a few thousand copies of the target antigen on the surface ? Do the current ADCs also kill those cancers ? The answer is – not well, and often not at all. Since many cancers have low density antigens on the surface, one has to increase the DAR to go after them. That is where Serina’s POZ-polymer ADC approach offers so much promise (see the animation below).
We begin with attachment of a “linker” to the toxin of interest. This linker has an azide group attached to it, allowing it to undergo quantitative attachment to the pendant alkyne group on the POZ polymer. This forms a stable triazole ring that does not break down in the blood, thus preventing premature release of the toxin. Once this is attached, we then attach the POZ-“warhead” polymer to specific sites on the antibody. These can be naturally occurring sites in the amino acid sequence of the antibody, or programmed sites for site-specific attachment. In the animation shown we have illustrated attachment of a POZ-“warhead” with five toxins undergoing attachment to two sites on the antibody, generating a DAR of ~ 10. But we can go much higher, and have created ADCs with DARs in excess of 30. We believe these ADCs will be very effective in killing cancers, and in particular those with low levels of expression of target antigens.
We have partnered our POZ-polymer technology with one of the top ten pharmaceutical companies in the world to develop some of the most promising next-generation ADCs.
We welcome an opportunity to show you how we do this. Please contact us at BD@serinatherapeutics.com for a discussion on how we might work together to cure cancer.